Table of Contents

Background

The American Heart Association estimates that more than 81 million American adults (one-third of all adults) have at least one form of cardiovascular disease (CVD).1 CVD is broadly defined to include all the disorders of the arterial system, including the heart and coronary arteries, the arterial supply to the brain, and the peripheral arterial system. CVD manifests typically as hypertension, angina, myocardial infarction (MI), heart failure, stroke and transient ischemic attacks (TIAs), and intermittent claudication or blockage. While there has been progress in the control of CVD, it demands huge investments from the health care system, and represents great burdens and lost opportunities for individuals, families, and society overall.

In addition to lifestyle and dietary recommendations, frontline treatment for prevention and treatment of CVD is primarily pharmaceutical, with patients requiring, on average, 6.3 concomitant prescription drugs from, on average, 5.9 different drug classes for primary and secondary prophylaxis of the disease itself and management of associated comorbidities.2-4

Complementary and alternative medicine (CAM) refers to preventive and therapeutic modalities not generally considered to be part of conventional medicine,5 including dietary supplements. CAM utilization has increased dramatically in North America over the past decades in both the general and CVD populations.6,7

The National Health Interview Survey indicated that Americans spent a total of $34 billion out of pocket on CAM in 2007.8 Estimates suggest that approximately one-third to two-thirds of people suffering from heart failure or other cardiovascular disease use dietary supplementation and are thus placed at risk for potential adverse events from interactions with other pharmacologically active agents and nonadherence associated with polypharmacy.7,9-13 With compromised physiology due to aging, the elderly are most vulnerable to the adverse events of any drug interaction. On the other hand, addition of a dietary supplement to conventional cardiovascular drugs may confer benefit. Evidence of both benefits and harms of adding a supplement to cardiovascular drugs has been reported.6,14

Incorporation in clinical practice of knowledge regarding the impact of concomitant use of cardiovascular medications and dietary supplements requires access to reliable drug-supplement information, as well as physicians’ commitment to documenting patients’ supplement use.15,16 While a substantial amount of research and data is available describing drug–drug interactions in various populations, the evidence for drug–supplement interactions or simply add-on supplement effect is unclear, especially in the CVD populations.

Objectives

The objective of this Comparative Effectiveness Review was to systematically synthesize and grade the strength of evidence of benefits and harms of adding a dietary supplement to cardiovascular drugs routinely prescribed in outpatient settings. A related objective included assessment of whether the altered outcomes of efficacy and/or effectiveness and harms are a result of a simple add-on effect of a dietary supplement or more complex interactions with the cardiovascular drug. Supplement–drug interactions were examined by investigating evidence of statistical and pharmacokinetic interactions.

These objectives were framed in the following Key Questions.

In adults taking cardiovascular drugs, what are the effects of concomitant use of specific dietary supplements (when compared with cardiovascular drugs alone or cardiovascular drugs and a different dietary supplement[s]) on:

Key Question 1

–Clinical cardiovascular effectiveness/efficacy outcomes (e.g., mortality and specific cardiovascular or cerebrovascular conditions such as myocardial infarction and stroke)?
(a) Do the effect estimates of clinical cardiovascular outcomes vary by age, ethnicity, gender, or health status?
(b) Is there a measurable interaction between cardiovascular drugs and dietary supplements for clinical cardiovascular outcomes?

–Pharmacokinetic outcomes (e.g., half life [t1/2], area under the concentration curve [AUC]) of cardiovascular drugs of interest?
(a) Do the effect estimates of pharmacokinetic outcomes vary by age, ethnicity, gender, or health status?
(b) Is there a measurable interaction between cardiovascular drugs and dietary supplements for pharmacokinetic outcomes?

Analytic Framework

The expectations behind using a dietary supplement with prescription cardiovascular drugs are improvement in the disease process (or its prevention) and reduction in harms related to cardiovascular drugs. These effects might come about through either an add-on effect of a supplement or its biological interaction with a cardiovascular drug. Benefits and harms are measured as outcomes that may be clinical outcomes, their proxy surrogates, or pharmacokinetic parameters. The analytic framework in Figure A depicts the causal pathways forming the basis of the Key Questions.

Methods

Input From Stakeholders

Preliminary broad searches identified the necessity to focus this review, so we formulated the population, intervention, comparator, and outcome (PICO) analytic framework and Key Questions in consultation with the Key Informants during a topic refinement stage. The range of dietary supplements was narrowed to include only those most commonly taken along with cardiovascular drugs and for which there was no recent review. A fifth Key Question, regarding P450 isozyme activity and cellular drug transport mechanisms, was dropped. The Key Informants included clinicians (cardiologists, naturopathic doctors, clinical pharmacology specialist, and nutritionist), a patient/consumer advocate, and systematic review research methodologists. The public were invited to provide comments on the Key Questions. During the review process, we followed an a priori research protocol developed with the clinical and methodological input of a Technical Expert Panel (TEP) of specialist clinicians and methodologists. The protocol followed the Effective Health Care Program’s Methods Guide for Effectiveness and Comparative Effectiveness Reviews.17

Data Sources and Searches

We searched the following electronic databases from inception to September 1, 2011: MEDLINE®, Embase, the Cochrane Library (CENTRAL, CDSR, DARE, and HTA), International Bibliographic Information on Dietary Supplements (IBIDS), and Allied and Complementary Medicine Database (AMED). We developed peer-reviewed search strategies (shown in Appendix A of the full report) using a broad range of controlled vocabulary to address the various synonyms associated with this topic, as well as to cover any evolutionary gaps associated with the introduction of certain vocabulary terms. We also searched trial registries (e.g., ClinicalTrials.gov, Current Controlled Trials, Clinical Study Results, World Health Organization Clinical Trials), the Cambridge Scientific Abstracts Conference Papers Index, and Scopus.

Results were refined using filters for systematic reviews, randomized controlled trials (RCTs), non-RCTs and observational studies, and safety. A more specific strategy related solely to herb-drug interactions was run in the same databases using only a systematic review filter.

We also contacted TEP members and the Scientific Resource Center at the Agency for Healthcare Research and Quality.

Study Selection

Two reviewers screened titles, abstracts, and full-text reports, with conflicts resolved by consensus or third-party adjudication. A primary study was eligible if it:

Was published in English or German.

Examined a dietary supplement. A dietary supplement was defined as a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance, or a concentrate metabolite, constituent, or extract intended to increase the total dietary intake made for ingestion in pill, capsule, tablet, powder, or liquid form not represented for use as conventional food or as the sole item of a meal or diet).

Compared the effect of adding a dietary supplement to cardiovascular medication(s) to the same cardiovascular medication(s) or to another dietary supplement (from the list above) added to the same cardiovascular medication(s).

Evaluated use of a dietary supplement intended for ingestion as pill, capsule, tablet, powder, or liquid. The dietary supplements considered were coenzyme Q10, Echinacea, garlic, ginger, Ginkgo biloba, Panax ginseng, American ginseng, hawthorn, oral magnesium, niacin (no more than 250 mg/day), omega-3 fatty acids/fish oils, red yeast rice extract, resveratrol, vitamin A, vitamin D with or without calcium, vitamin E, and vitamin K. This list was selected after extensive discussions with the TEP and reference to surveys of the general and cardiovascular populations in the Unites States.7,18-23

Included cardiovascular drugs that were commonly used in outpatient settings (Table 1 of full report).

Reported clinical or surrogate cardiovascular efficacy or harms, or pharmacokinetic outcomes, in any adult population.

Was a randomized controlled trial, nonrandomized trial, or observational study with an independent concurrent or historical control group including at least five participants. For Key Question 4, studies employing participants as their own controls were also eligible. (This was a post hoc decision in light of the relevance of this design for study of pharmacokinetic interactions.)

Good-quality English language systematic reviews on the topic were also eligible. However, a systematic review could replace de novo synthesis of evidence only when the review was deemed to be current, obviating the need to update it.

Studies included after full-text screening were removed from data synthesis because of one or more of the following reasons:

Cardiovascular drug(s) were not taken by at least 80 percent of participants in RCTs. Including such studies would have severely limited the applicability of evidence.

The study reported effect estimates that did not reflect a comparison of supplement plus drug(s) versus drug(s) alone (or plus another supplement).

No relevant outcome was reported in the study or the outcome data were not received from the authors of the studies. (Authors were contacted for data clarification and additional outcome data when data were recognized to have been recorded but not reported in the published study—for example, outcome data without a measure of dispersion.)

The design of the study was lower in the hierarchy of evidence (i.e., nonrandomized experimental or observational study in the presence of higher quality RCT evidence) and did not meaningfully add to the evidence already included by being a longer term or pragmatic study reporting conclusive results.

Studies included cardiovascular drugs not marketed in the United States.

Administration dose and/or frequency of the dietary supplement was not quantified.

Data Extraction and Risk-of-Bias Assessment

One reviewer extracted relevant data from each study and a second reviewer independently verified data for a 10 percent random sample of studies. Extraction items included general study characteristics (e.g., year of publication, study design); population characteristics (e.g., inclusion/exclusion criteria, age, race, level of activity, condition); intervention characteristics (e.g., dose, duration, details about comparators, level of care); and outcomes (i.e., clinical and surrogate outcomes of efficacy and harms, and pharmacokinetic outcomes) with their estimates. During the data extraction process, one reviewer with a clinical background rated study populations’ 10-year coronary heart disease (CHD) risk according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines.24

We assessed study risk of bias according to outcome, using generic items for confounding and various types of bias (e.g., selection, performance, detection, and attrition bias) separately for each study design. Selected items from the McMaster Quality Assessment Scale of Harms were also incorporated into the risk-of-bias assessment for harm-related outcomes. Certain criteria were specific to particular study designs; for example, allocation generation and concealment applied only to RCTs.25 For gradable outcomes, one reviewer rated the overall risk of bias for the study as low, moderate, or high risk, and a second reviewer independently verified the assessment. Outcomes were rated as high risk of bias if there was an apparent and major flaw in the study that would invalidate results. Appendix C in the full report provides the detailed individual study data and risk-of-bias ratings.

Grading the Strength of the Body of Evidence and Applicability

In principle, a body of evidence originating in randomized trials starts with a presumed high strength of evidence and is downgraded across the domains when there is important overall risk of bias for contributing studies, inconsistency in the direction of the intervention effect, indirectness of the outcome of interest (e.g., a surrogate outcome rather than a clinical health outcome), or imprecision in effect estimates of an extent that neither important benefit nor harm can be ruled out. For nonrandomized studies, the body of evidence starts with a presumed low strength of evidence but may be upgraded across certain domains. The strength of a body of evidence was graded based on the following four domains, per published guidance: overall risk of bias by outcome, consistency, directness, and precision.26

Gradable important outcomes for this review were identified a priori in consultation with the TEP (Table A). This was done because customarily only a subset of important outcomes that are more meaningful for decisionmaking concerning each specific Key Question are chosen.26

A methodologist and a content expert graded the strength of the body of evidence as “high,” “moderate,” “low,” or “insufficient.” From a larger list of outcomes of interest for each Key Question (see the Methods section of the full report).26,27

The strength of evidence was graded insufficient when there was no evidence for an outcome, when the direction of the estimates was inconsistent between studies without an identifiable cause, or when the body of evidence from the contributing study/studies was underpowered for the outcome of interest (imprecise estimate). When an effect estimate was associated with a confidence interval (CI) that was not only nonsignificant, but wide enough that the clinical action would differ if the upper versus the lower boundary of the CI represented the truth, we rated the effect as imprecise. This reflected our uncertainty regarding clinically important benefit or harm, or a clinically unimportant difference in effect estimates between the contrasting interventions.

Following published guidance, we summarized the determinants of applicability of the body of evidence for outcomes with conclusive results.28 Studies that evaluated representative patient populations in usual or routine care conditions and lasting long enough to meaningfully measure health outcomes of both benefits and harms were considered pragmatic or effectiveness studies. In contrast, studies examining intermediate efficacy outcomes in highly selected patients were considered efficacy studies.29

Data Synthesis and Analysis

All analyses compared the combination of dietary supplement plus cardiovascular drug with cardiovascular drug alone or plus placebo or plus another dietary supplement. Meta-analyses were carried out when there was clinical and methodological homogeneity. For pharmacokinetic outcomes, we followed the U.S. Food and Drug Administration (FDA) guidance for analysis and interpretation of drug interaction studies—that is, the zone of bioequivalence is recommended to be between the lower and upper bound of the 90 percent geometric mean ratio (GMR), with a CI between 0.8 and 1.25.30

We did not pool experimental and observational studies, but did pool parallel studies with valid crossover randomized trials. We did not consider precrossover data for synthesis except when it was judged that the treatment given to participants in a given crossover trial was not appropriate for the condition under consideration.31,32 Similarly, we did not pool crossover trials that had not employed a sufficient washout period between the two treatment periods because of bias arising from carryover treatment effects. We did not meta-analyze observational studies because of the differences in adjustment for confounders and residual confounding.

Meta-analysis was considered when studies were randomized trials that included similar populations, compared the same type of dietary supplement versus comparator treatment, and reported the same outcome measures in the same statistical format (e.g., mean difference or GMR). Relative risk (RR) and post-treatment mean differences (MDs) were meta-analyzed using the DerSimonian and Laird random-effects model,33 and Peto odds ratios were calculated when event rates were less than1 percent.32

For studies with zero events in some arms or sparse data overall, we pooled using the fixed-effects Mantel-Haenszel method without continuity correction.34 Studies with zero events in both arms were excluded from meta-analysis.32 Where applicable, we examined statistical heterogeneity by calculating the synergy index (detailed in the Methods section of the full report).35 The synergy index estimates the supplement-drug statistical interaction when the effect observed with the combination is of a magnitude that is greater than or less than would be anticipated in an additive model, knowing the independent effects of the supplement and drug. An S-index (ratio of effects measured to additive calculation) greater than 1 describes a positive interaction (synergism), and an S-index less than 1 indicates a negative interaction (antagonism). Statistical heterogeneity was assessed using Cochran’s Q (α = 0.10) and the I2 statistic.

Outcome results were considered to be inconclusive when the pooled estimate or the single contributing study estimate had confidence intervals wide enough to incorporate both clinically important benefit and harm (i.e., type II error suggesting underpowered studies unable to precisely conclude benefit, harm, or no difference between treatments). Results were also considered to be inconclusive when studies could not be pooled—for example, when similar outcomes were reported in different statistical formats in studies or study results pointed in opposite directions. When inconclusive results were associated with a gradable outcome, strength of evidence was deemed insufficient.

Results

Overview

The PRISMA flow diagram summarizes the number of records screened and included (Figure B).

In total, 38,984 records were identified by searches of databases (including gray literature, reference list checking, and search for systematic reviews and meta-analyses) and screened for eligibility. Seventy unique English-language studies (in 80 published articles), including one of observational design, contributed evidence. No systematic reviews were found to be eligible for evidence synthesis. Additionally, we found no relevant unique German publications. Twenty-two studies contributed to meta-analyses in this review.

Table B shows the most relevant risk-of-bias criteria for the randomized and controlled clinical trials included (n = 69).

Table B. Risk-of-bias criteria and conflict of interest for all RCTs and CCTs

Twenty-one randomized controlled trials contributed evidence for Key Question 1.36-56 No data were available from observational studies. Generally, across all combinations of dietary supplements and cardiovascular drugs, the strength of evidence of the gradable outcomes of comparative efficacy or effectiveness was graded insufficient. Type II error could not be excluded due to the low statistical power of mostly short-term efficacy trials. In addition, strict inclusion criteria excluded patients with uncontrolled comorbidities and acute ischemic events.

Coenzyme Q10: Insufficient evidence was found for the effect of coenzyme Q10 coadministered with angiotensin-converting enzyme (ACE) inhibitors on all-cause mortality and quality of life in 30 mostly male patients with left ventricular dysfunction over a 3-month period.54 Adherence to simvastatin with or without supplement coadministration was 98 percent during a 12-week pilot study in 22 patients with previous statin-related myalgia.38

Ginkgo biloba: With no deaths observed, insufficient evidence for mortality was found for G. biloba coadministered with aspirin and/or pentoxyphilline during a 4-week underpowered study in 33 South Asians with previous ischemic stroke.48

Magnesium: In a crossover trial of oral magnesium aspartate or placebo administered daily for 8 weeks to a selected group of 40 hypertensive patients with no comorbidities on therapeutic doses of beta-blockers, a single event of myocardial infarction was noted.42

Omega-3 fatty acids: Insufficient evidence from underpowered efficacy studies addressed the outcomes of mortality (in 50 healthy men)36 and arrhythmia (in 122 highly selected dyslipidemic patients)40 when omega-3 fatty acids were coadministered with statins. In three short-term efficacy trials of omega-3 fatty acid and statin coadministration, statin adherence as judged by pill count was found to be greater than 95 percent in both treatment groups.37,44,53

Insufficient evidence from single efficacy trials did not demonstrate a difference in the outcome of all-cause mortality when study cardiovascular drugs were aspirin (291 high-risk patients followed for 1 year with 9 deaths), warfarin (319 high-risk patients followed for 1 year with 5 deaths), and fenofibrate (unclear 10-year CHD risk in 167 participants with hypertriglyceridemia followed for 8 weeks with no deaths).47,56

Vitamin K: Insufficient evidence was found for mortality and stroke. In one 6-month efficacy trial in 70 selected groups of patients with unstable international normalized ratios (INRs) anticoagulated with warfarin with coadministered vitamin K, no stroke and 1 death were observed.41

Other supplement-cardiovascular drug combinations and outcomes: Three notable trials reported outcomes that were not a priori gradable outcomes.

One pragmatic trial in 19,934 women randomized to vitamin E plus aspirin versus aspirin alone for 10 years noted no significant differences for the composite outcome of nonfatal myocardial infarction, nonfatal stroke, and vascular death (RR, 0.95; 95 percent CI, 0.79 to 1.13).39 Although components of the composite outcome were gradable, it was not possible to discern if shifts in the incidence of stroke and heart attack might have been obscured in this composite outcome.

Inconsistent evidence on rates of restenosis following successful coronary angioplasty, best explained by differences in study population, design, and treatment, was found with omega 3 fatty acids added to conventional antiplatelet therapy and calcium channel antagonists.51,52 When 82 highly selected male patients took omega-3 fatty acids daily along with therapeutic doses of aspirin, dipyridamole, and calcium channel antagonists, significantly lower rates of restenosis (at least 50 percent reduction in diameter) were observed compared with the cardiovascular drugs alone (RR, 0.40; 95 percent CI, 0.20 to 0.82); however, the mean percentage reduction in luminal diameter was not significantly different between the two groups.52 No differences were noted in rates of restenosis when a similar but lower quality trial was conducted in 107 South Asians in India who were not taking dipyridamole.51

Underpowered studies addressed other outcomes that were not graded per the a priori protocol. These included exacerbation of congestive heart failure, number of patients undergoing cardiac procedures, graft occlusion, neurologic recovery score, coronary vasospasm, and number of angina attacks for various dietary supplement and cardiovascular drug combinations. Most studies were short-term efficacy trials.

No data were identified for hospitalization or peripheral arterial disease for any supplement-cardiovascular drug(s) combination.

No evidence on outcomes of clinical efficacy/effectiveness was found for Echinacea, garlic, ginger, ginseng, hawthorn, supplemental doses of niacin (not more than 250 mg/day), red yeast rice extract, resveratrol, vitamin A, or vitamin D (with or without calcium) supplementation coadministered with a cardiovascular drug.

A paucity of studies of supplement-drug combinations for which data were available precluded exploration of heterogeneity in terms of preidentified subgroups or documentation of any dose-response effect.

Key Question 1b. Is there a measurable interaction between cardiovascular drugs and dietary supplements for clinical cardiovascular outcomes?

No study analyzed statistical interactions between a supplement and a cardiovascular drug in terms of clinical outcomes.

Fifty-seven RCTs and two non-RCTs were included for this Key Question. No relevant observational study was identified. Study participants in most studies had mixed (low and/or moderate) or unclear CHD risk (27.1 percent and 37.3 percent, respectively).Study quality was variable. In the majority of RCTs, the generation of allocation sequence (78 percent) and allocation concealment (93 percent) were unclear. In about 20 percent of studies, participants, health care providers, or outcome assessors were blinded to treatment allocation. This information was not clear for 56 percent of the studies.

The majority of evidence on intermediate outcomes was contributed by small underpowered RCTs whose statistically nonsignificant results with wide confidence intervals could rule out neither important benefits nor harms. Due to this imprecision, the strength of evidence for several gradable outcomes was rated insufficient (inconclusive results). When a significant effect was observed, we graded the strength of evidence to be low because of limitations in the internal validity of studies, surrogacy of outcomes, and generally poor to absent reproducibility among studies in the direction of effect estimates (Table D). None of the studies reported outcomes evaluating incidence of metabolic syndrome, incidence of hypotension, carotid-intima media thickness, or change in 10-year Framingham risk profile.

Coenzyme Q10: Evidence was available from four RCTs with unclear CHD risk (49 Asians with hypercholesterolemia57), mixed CHD risk (44 participants with statin-induced myalgia38), and high CHD risk (40 participants with diabetes and dyslipidemia58 and 30 participants with ischemic or idiopathic dilated cardiomyopathy54). Overall, no significant differences (grade: insufficient; results inconclusive) were seen between the combination of coenzyme Q10 plus a cardiovascular drug versus drug alone in post-treatment levels of:

Lowgrade evidence was avaiable from one trial indicating no significant difference in high density lipoprotein-cholesterol (HDL-C) for the combination of coenzyme Q10 plus fenofibrate versus fenofibrates alone.

Echinacea: In one small study in 12 healthy male participants (low CHD risk),59 post-treatment levels of INR and platelet aggregation were not significantly different in the combination of Echinacea plus warfarin than with warfarin alone. The results were inconclusive.

Garlic: Four studies examined the effects of garlic in combination with warfarin (48 participants with unclear CHD risk60 and 16 males with low CHD risk61), nitrates (60 participants with high CHD risk62), and statins plus aspirin (19 participants with high CHD risk63).

The effects of garlic combined with statins plus aspirin63 on lipid profile, C-reactive protein, platelet count, and Agaston calcium score were not significantly different from those of statins plus aspirin in participants with coronary artery disease (Framingham risk >20 percent).

Ginger: In one trial of 12 healthy male participants there was no significant difference in post-treatment INR (inconclusive; grade: insufficient) or platelet aggregability between participants taking the combination of ginger plus warfarin versus warfarin alone.64

Ginseng: Three RCTs investigated various ginseng products in combination with warfarin.69-71 The results from these studies for INR were conflicting (inconclusive; grade: insufficient). Two trials showed no significant difference (25 participants with high CHD risk,69 12 males with low CHD risk71). One trial (20 participants with low CHD risk70) showed a significant difference, with lower peak INR and AUC of INR in the combination versus control group (MD, -0.19 [95 percent CI, -0.36 to -0.07] for peak INR and -0.43 [95 percent CI -1.00 to -0.09] for AUC of INR). The differences in prothrombin time,69 platelet count,69 or platelet aggregability71 between the ginseng-warfarin combination and warfarin-only groups were not significant (results were inconclusive).

Hawthorn: One small trial72 found no significant difference in an ECG measure (PR interval, which is measured from the beginning of the P wave to the beginning of the QRS complex) between participants receiving hawthorn plus digoxin and those receiving digoxin alone (results inconclusive) in 11 adults at low risk for CHD.

Magnesium: Three RCTs investigated oral magnesium in combination with hydrochlorothiazide73,74 or beta-adrenergic antagonists42 in participants with hypertension. In two trials, SBP and DBP (diastolic blood pressure) did not differ significantly between the magnesium hydrochlorothiazide combination versus hydrochlorothiazide-alone groups in the study with 18 participants with unclear CHD risk73 or the study with 21 participants with low/moderate CHD risk74 (inconclusive; grade: insufficient). Similarly, in another study,42 neither SBP nor DBP was significantly different in 39 participants receiving the combination of magnesium plus beta-adrenergic antagonists versus those receiving beta-adrenergic antagonists alone. In one trial,73 post-treatment total cholesterol and triglyceride levels were not significantly different between the magnesium-hydrochlorothiazide combination versus hydrochlorothiazide-alone groups (inconclusive; grade: insufficient).

Niacin (no more than 250 mg/day): One RCT in 28 participants with hyperlipoproteinemia (unclear CHD risk)75 investigated niacin in combination with propranolol. Post-treatment levels of triglycerides and total cholesterol were not significantly different between the group receiving niacin plus propranolol and the groups receiving propranolol alone (inconclusive; grade: insufficient). This study was judged to be at high risk of bias because groups were administered different dosages of propranolol (20 mg and 60 mg).

The effect on post-treatment triglyceride (TG) levels of adding the supplement to statins was modified according to baseline levels of triglycerides. Specifically, in participants with higher mean baseline levels of TG (greater than 200 mg/dL) there was a statistically significant pooled mean reduction in post-treatment TG levels in the combination arm (two trials, grade: low).40,76 In contrast, the meta-analysis of four studies with participants with lower levels of TG at baseline (under 200 mg/dL) showed no significant difference between the groups (grade: insufficient). Pooled analyses for levels of HDL-C (seven trials), LDL-C (six trials), and total cholesterol (six trials) showed no significant differences (grade: low) in participants with mixed or unclear CHD risk. The mean SBP was significantly lowered in the supplement-statin combination group (grade: low) in 22 participants with hyperlipemia. Evidence was inconclusive for the outcomes of total cholesterol/HDL-C ratio, non-HDL-C, lipoprotein A, diastolic blood pressure, and bleeding time. Additionally, for nongradable outcomes such as C-reactive protein and blood coagulation parameters (prothrombin time (PT), activated partial thromboplastin time [aPTT], platelet aggregation), there were no significant differences between combination and control groups.

In trials using omega-3 fatty acids-ACE inhibitors combination treatment, there were no changes in blood pressure (no difference; grade: low), but significantly more participants experienced at least 50 percent reduction in proteinuria in favor of the combination treatment (RR, 4.00 [95 percent CI, 1.40 to 11.30]).77

In one trial using omega-3 fatty acids-fenofibrate combination treatment in participants with high triglyceride levels,56 the incidence of hypertension was not significantly different in the combination versus control group (RR, 0.98 [95 percent CI, 0.14 to 6.85]).
In one trial50 using omega-3 fatty acids-calcium channel blockers combinations, there was no significant difference between the combination and control groups in post-treatment lipid profile (inconclusive; grade: insufficient). Two other trials using aspirin in addition to calcium channel blockers found significant differences in triglycerides (grade: low) in favor of the combination treatment.51,52 These trials were not pooled because dipyridamole was an additional drug in one trial and not in another.

The effect of vitamin E-furosemide combination on blood pressure was not significantly different from that of furosemide alone in 24 participants with essential hypertension (inconclusive; grade: insufficient).81 The vitamin E-nifedipine combination significantly lowered total cholesterol (MD, -35.96 mg/dL [95 percent CI, -46.96 to -24.96]), LDL-C (grade: low), and triglycerides (grade: low), but not HDL-C (inconclusive, grade: insufficient) or SBP (inconclusive, grade: insufficient) in 30 elderly subjects at high risk of CHD.82

There was no significant difference in lipid profile across trials using vitamin E-gemfibrozil or vitamin E-statins combinations when compared with the cardiovascular drug alone (inconclusive; grade: insufficient). (See pooled analyses for HDL-C, LDL-C, total cholesterol, and triglycerides.) Likewise, there was no significant difference in blood pressure (inconclusive; grade: insufficient) for vitamin E-gemfibrozil combination, and no significant difference in C-reactive protein, prothrombin time, and platelet count for vitamin E-statins combinations compared with cardiovascular drug(s) alone.

Vitamin K: In one trial,41 percentage of time INR was in therapeutic range was improved in the group receiving vitamin K-coumarin derivative (warfarin) combination compared with warfarin alone. In addition, number of participants achieving stable INR was higher in combination than with warfarin alone.

Sparse evidence precluded exploration of heterogeneity in the effect estimates for harms across preidentified subgroups.

Key Question 2b. Is there a measurable interaction between cardiovascular drugs and dietary supplements for intermediate cardiovascular efficacy outcomes?

Two studies contributed to the evidence regarding statistical interaction between cardiovascular drugs and dietary supplements for this section.44,78 One study assessed statistical interaction using general linear modeling.44 No significant interactions were observed between the combination of omega-3 fatty acids and statins with regard to changes in lipid profile (HDL-C, LDL-C, total cholesterol, triglycerides, non-HDL-C) in 52 obese men with dyslipidemia and insulin resistance (moderate/moderately high risk for CHD).44 Authors of another trial78 conducted a formal assessment of statistical interaction using ANOVA (analysis of variance) and found that the decrease in triglyceride levels resulting from the combination of omega-3 fatty acids plus niacin was more than twice the additive effect of either therapy alone in 29 participants with atherogenic dyslipidemia (unclear CHD risk).

A total of 58 studies contributed evidence for Key Question 3. One included study was a retrospective cohort study examining omega-3 fatty acids and antiplatelet agents; it had important limitations in design and reporting, as it was unclear regarding participant selection, confounding, and blinding of outcome assessors.88 The rest of the studies were RCTs, mostly of moderate risk of bias for the gradable outcomes of harms (serious adverse events, withdrawal due to adverse events, renal dysfunction, hepatotoxicity, QT interval, and bleeding). Most of these studies recruited a small number of participants and were underpowered for the outcomes of harm.

Meta-analyses were possible for some omega-3 fatty acids studies. Other evidence could not be pooled because either there was a single study per outcome or zero events in both treatment arms.

For all combinations of dietary supplement and cardiovascular drug, the strength of evidence for all gradable outcomes was insufficient due to inconsistent effect estimates across studies suggesting conflicting findings with no obvious explanation or statistically nonsignificant estimates with wide confidence intervals (Table E). Most crossover trials incorporated an adequate washout period, so carryover effect was not a major concern.

Coenzyme Q10: Five short-term (up to 12 weeks duration) small RCTs that included participants with mixed (moderate and high risk)/unclear38,57,89 or high 54,58 CHD risk examined coenzyme Q10 plus statins, fenofibrate, ACE inhibitors, or, in one study, vitamin E added to statins. No statistically significant differences were observed for total adverse events,54,57 abnormalities in fasting blood glucose,57,58 myoglobin,57 creatine phosphokinase (CPK),57,58,89 electrocardiogram (ECG),58 or retinopathy.58 However, the studies were underpowered to detect differences in these harms.

Echinacea: One small RCT of 12 healthy volunteers examined Echinacea plus a single dose of warfarin versus warfarin alone. No withdrawals due to adverse events or other adverse events were observed.59

Garlic: Four small short-term RCTs examined garlic in combination with warfarin, nitrates, or statins plus aspirin in healthy males61 or those with cardiovascular conditions.60,62,63 No significant between-group differences were observed across gradable and nongradable outcomes such as fasting blood glucose,60,62,63 anemia,60 and leukopenia.63 Wide confidence intervals for differences in bleeding and fasting blood glucose precluded drawing any meaningful conclusions.

Ginkgo biloba: Seven small RCTs examined G. biloba plus warfarin, digoxin, aspirin, aspirin and/or pentoxiphylline, nitrates, cilostazol or clopidogrel, or ticlopidine.48,64-68,90 The subjects either were healthy volunteers,64,65,67,68,90 had experienced acute ischemic stroke,48 or had peripheral arterial disease.66 Two of these studies included only a single dose of cilostazol/clopidogrel67 or ticlopidine,68 so their results should be interpreted with caution. Across all cardiovascular medications, nonsignificant results were observed for gradable outcomes (i.e., withdrawal due to adverse events, bleeding, renal dysfunction, hepatotoxicity, and serious adverse events). Nonsignificant results were also found for all other harms, such as total adverse events,66,67,90 upset stomach,66 anemia,65,66 abnormal white blood cell count,65 gastrointestinal events,48,90 diarrhea,64 constipation,64 hypoglycemia,66 hyperglycemia,66 leukopenia,66 thrombocytopenia,66 and abnormal ECG.66 These studies were underpowered to detect any differences in harms outcomes.

Ginseng: Three RCTs examined the effects of Panax ginseng,69,71 American ginseng,70 and Korean ginseng71 plus warfarin versus warfarin alone. No statistically significant effects were observed in gradable outcomes (i.e., withdrawal due to adverse events, bleeding, renal dysfunction, and hepatotoxicity) or nongradable outcomes such as prothrombin time, total adverse events, headache, dizziness, indigestion, INR above 3.5, diarrhea, constipation, hematocrit, and anemia.69 These trials were all small and underpowered.

Niacin (not more than 250 mg/day): One RCT of 20 subjects with hyperlipoproteinemia investigated the effects of niacin plus propranolol versus propranolol alone.75 No statistically significant differences were found in nausea and flushing or in hypotension. This study was at high risk of bias because groups received different dosages of propranolol (20 mg in combination group and 60 mg in monotherapy group).

Vitamin E: Ten RCTs examined vitamin E plus aspirin,39,49,100 nifedipine,82 furosemide,81 or statins.46,83,84,86,87 No statistically significant differences were observed for total adverse events,100 incidence of headache,100 gastrointestinal discomfort,100 incidence of cancer,39 abnormalities in fasting blood glucose,81,82 glycosylated hemoglobin,87 leukopenia,46 or anemia.46 These studies recruited subjects who were healthy, or who had CHD or risk factors for CHD. Sample sizes were generally small, except for one study that recruited over 9,000 women.39

Vitamin K: One RCT of 6 months duration examined the effects of vitamin K plus warfarin versus warfarin alone.41 No significant differences were found for bleeding41 or withdrawal due to adverse events.41 This study recruited 70 participants with indications for anticoagulant therapy.

Other supplements: No evidence on clinical harms was identified for the effects of ginger, red yeast rice extract, resveratrol, vitamin A, or vitamin D in combination with cardiovascular drugs.

Key Question 3a. Do the effect estimates of clinical or intermediate harms vary by age, ethnicity, gender, or health status?
Sparse evidence precluded exploration of heterogeneity in the effect estimates for harms across preidentified subgroups.

Key Question 3b. Is there a measurable interaction between cardiovascular drugs and dietary supplements for harms outcomes?

One RCT presented data that would allow examination of the interaction between vitamin E supplements and the cardiovascular medication aspirin. This RCT found no significant difference in the rates of adverse events (headache, gastrointestinal discomfort, and withdrawal due to adverse events) among treatment regimes.100

Twelve randomized controlled trials contributed evidence on pharmacokinetic outcomes.36,59,61,64,68,70-72,90,93,95,101 No data were available from observational studies. Generally, these studies were open-label crossover RCTs of moderate risk of bias for the gradable outcomes, including between 8 and 50 healthy volunteers. Six studies investigated cardiovascular drug kinetics following a single dose.59,61,64,68,71,90 The clinical significance of the interaction was evaluated using the FDA guidance.30 According to this guidance, the statistical significance of interactions alone cannot determine the clinical significance of interactions. Interactions are deemed significant when the 90 percent confidence intervals of the geometric mean ratio (GMR) fall clearly outside of the default no-effect range of 0.80 to 1.25.

It must be noted that the evidence of pharmacokinetic interactions may not translate into altered clinical effectiveness or harms. Also, evidence originating in healthy young adults may not be applicable to older CVD patients taking cardiovascular drugs due to possible differences in abilities to absorb, metabolize, and excrete drugs.

Echinacea: Evidence of low strength demonstrated no clinically significant interactions between a mixture of 600 mg of Echinacea angustifolia root plus 675 mg of E. purpurea root given four times a day for a period of 2 weeks and a single dose of 25 mg warfarin. The 90 percent upper and lower bound of GMR for the individual warfarin pharmacokinetic parameters were within the 0.80 to 1.25 boundaries of bioequivalence (Table F).59

Garlic: Interactions of 7.4 mg/day of allicin pretreatment for 2 weeks with a single dose of 25 mg warfarin are unclear. Low-strength evidence suggested no clinically relevant interactions for some pharmacokinetic outcomes, while for other important outcomes the strength of evidence was graded as insufficient.61 Evidence from one garlic-statin trial demonstrated insufficient evidence for pharmacokinetic interactions between the supplement (3600 mg of allicin twice daily) and 20 mg single doses of both simvastatin and pravastatin.101 Interactions and bioequivalence could not be clearly established.

Ginger: Evidence of low strength demonstrated no clinically significant interactions between 7-day pretreatment with ginger and a single 25 mg dose of warfarin.64

Ginkgo biloba: Evidence of low strength demonstrated no clinically significant interactions between 7-day pretreatment with G. biloba and a single 25 mg dose of warfarin.64 Low-strength evidence revealed no clinically significant interactions between single doses of G. biloba and ticlopidine.68 Insufficient evidence addressed interactions between 7-day pretreatment with G. biloba and single doses of digoxin. While pharmacokinetic outcomes showed statistically nonsignificant changes, data were not reported as GMRs, so meaningful conclusions could not be drawn.90

Ginseng: Panax ginseng (Korean ginseng) coadministered with warfarin demonstrated no clinically significant interactions based on evidence of low strength.71 In contrast, interactions of American ginseng (P. quinquefolius 2 g/day from weeks 2 to 4) with warfarin were unclear. Low-strength evidence suggested no clinically relevant interactions for some pharmacokinetic outcomes, while for other important outcomes the strength of evidence was graded as insufficient.70

Hawthorn: In a trial of hawthorne (84.3 mg/day of oligomeric procyanidines) added to digoxin for 21 days versus digoxin alone for 10 days, no significant differences in pharmacokinetic outcomes were observed between groups. As analyses evaluated mean differences instead of GMRs, we could not exclude type II error and graded the strength of evidence as insufficient for clinically significant interactions.72

Omega-3 fatty acids: Three open-label randomized crossover studies in 24 to 50 healthy adult volunteers investigated interactions between omega-3 fatty acids and various statins.36,93,95 Each study compared a statin (rosuvastatin, atorvastatin, or simvastatin) coadministered with 4 g/day of omega-3 fatty acids versus statin alone over a 14-day period. Insufficient evidence for interactions with simvastatin precluded meaningful conclusions about interactions because pharmacokinetic outcomes were analyzed as differences in arithmetic means, yielding nonsignificant results with potential for type II error.95 Interactions with rosuvastatin or atorvastatin were unclear because for some of the pharmacokinetic outcomes there was low-strength evidence suggesting no clinically relevant interactions, while for other important pharmacokinetic outcomes the strength of evidence was graded as insufficient.36,93

Other supplements: No studies were found examining pharmacokinetic interactions between a cardiovascular drug and coenzyme Q10, magnesium, niacin (no more than 250 mg/day), red yeast rice extract, resveratrol, vitamin A, vitamin D with or without calcium supplementation, vitamin E, or vitamin K.

A paucity of evidence for supplement-drug combinations precluded exploration of heterogeneity in terms of preidentified subgroups such as age and gender.

Key Question 4b. Is there a measurable interaction between cardiovascular drugs and dietary supplements for pharmacokinetic outcomes?

Statistical interaction data were not reported in any pharmacokinetic study.

Discussion

Patients with cardiovascular disease commonly take dietary supplements along with prescription drugs, but this review uncovered a paucity of high-quality research into benefits and interactions of drugs coadministered with some of the most common supplements. No trials were identified for most potential combinations, while those that were found were generally underpowered efficacy trials of short duration in highly selected populations.

Clinical outcomes were reported in a sparse collection of inconclusive trials; therefore, evidence on important gradable clinical outcomes was rated insufficient. Findings of note include inconsistent evidence of decrease in rates of coronary artery restenosis following successful angioplasty with coadministration of omega-3 fatty acids in two trials with aspirin and other cardiovascular drugs. Also, evidence from a well-powered pragmatic trial in women showed no benefit of adding vitamin E to daily aspirin on the composite outcome of nonfatal myocardial infarction, nonfatal stroke, and vascular death; evidence on individual vascular events was not available.

For most intermediate outcomes of efficacy, such as lipid profile, blood pressure, and INR, we found either insufficient evidence or evidence of low strength demonstrating no effect; however, evidence indicated that omega-3 fatty acids (2 to 4 g/day) likely do not interfere with the efficacy of statin therapy or calcium channel blockers in the presence of antiplatelet agents, but may provide independent benefit in resolving hypertriglyceridemia. There is evidence of low strength that supplemental vitamin K (0.1 to 0.15 mg/day) may help to stabilize INR when given with warfarin. Also, garlic (4 to 10 g/day) may not interact negatively with nitrates and warfarin, and may confer independent benefit in improving HDL-C and total cholesterol. However, our confidence in the validity and reproducibility of these benefits on intermediate outcomes is low.

Safety of intake of dietary supplements concomitant with prescription cardiovascular medications is largely unclear due to insufficient evidence. Evidence regarding benefit of coenzyme Q10 in reducing myalgia in participants with statin-induced myopathic pain is based on two small RCTs and is inconclusive. One study found benefit of supplementation of coenzyme Q10 versus vitamin E added to statins, while another pilot study reported no significant differences between groups using simvastatin with or without coenzyme Q10 in myalgia and tolerance for statin therapy.

Evidence of low strength demonstrated no clinically significant pharmacokinetic interactions when Echinacea, ginger, or Ginkgo biloba were coadministered with warfarin or when G. biloba was coadministered with ticlopidine. Insufficient or conflicting evidence addressed most other supplement-drug pharmacokinetic interactions.

Without an adequate evidence base from the literature, variability in effects across clinically important subgroups (e.g., age, ethnicity, gender, and health status) could not be assessed.

Limitations of our systematic review process include our restriction of the number of dietary supplements of interest to 16 of the most commonly used; this was necessary given limitations of resources and review time. Up to 30 percent of included studies were assessed to have potential for financial conflict of interest, and approximately 45 percent did not report funding information. Given the uncertainties involved in interpreting asymmetry tests for publication bias in most reviews, especially in the presence of heterogeneity in effect estimates, we did not plan to investigate publication bias in this review.102,103 In fact, a recent recommendation is that tests for funnel plot asymmetry should be used only in a minority of meta-analyses that include at least 10 studies of unequal sizes per analysis without substantial heterogeneity in their effect sizes.104 We did not adopt other means of evaluating publication bias and selective outcome reporting, such as comparing publications with study protocol, because of time and resource limitations. Seemingly, another limitation could be the exclusion of indirect evidence of drug interactions derived from surrogate measures, such as alterations in probe drug metabolism, that highlight effects on enzymes involved in drug metabolism. As such evidence traditionally originates in healthy volunteers, the applicability of such evidence would have been as much of a concern as for the pharmacokinetic outcomes we examined, whose applicability was restricted to healthy volunteers with uncompromised drug metabolism. In order to make causal inferences possible for translation into practice, we also excluded combinations of multiple dietary supplements with cardiovascular drugs. For example, a given combination of multivitamins coadministered with a cardiovascular drug or drugs would be limited both in causal inference of supplement–drug(s) interactions and in applicability to the specific doses and combinations of vitamins employed as intervention in the study. Finally, we considered potential benefits, harm, or bioequivalence independently for pharmacokinetic outcomes, according to the FDA guidance.30 In the absence of guidance regarding intermediate outcomes, we did not draw conclusions on the two sides of clinical decisionmaking, such as “unknown benefit but harm is unlikely” and “unknown harm but benefit is unlikely.”

Available evidence poorly addresses the safety and effectiveness of coadministration of dietary supplements with cardiovascular drugs. Given the steady increase in the use of dietary supplements for self-care and the identified gaps in research, we make the following recommendations for future research.

First and foremost, future research with dietary supplements should involve substances for which the identity of the agents can be clearly ascertained and the chemical composition well characterized and, ideally, standardized. If the active ingredients or biologic activity of these substances is not known, then studies to characterize these variables, identify mechanisms of action, and describe safety should precede clinical efficacy studies. According to the 2011–15 strategic plan of the National Center for Complementary and Alternative Medicine (NCCAM), clinical trials of dietary supplements will not be supported without documentation of biology and mechanism of action.105

As extant literature is largely based on few small-size efficacy studies of limited internal validity examining intermediate outcomes, future supplement–cardiovascular drug interaction trials should focus on meaningful clinical outcomes, be appropriately powered and rigorously conducted and reported, and provide precise measurements of both clinical effectiveness and harms outcomes.

Most studies were conducted in specialty settings, excluded patients with comorbidities or uncontrolled comorbidities, and did not include ethnic and racial minorities; prospective trials should be representative of the population taking cardiovascular drugs in terms of comorbidities, setting, and racial distribution. They should also collect data and undertake subgroup analysis for age, gender, race, comorbidities (e.g., liver or renal compromise), and genotypic polymorphisms of the cytochrome P450 enzyme.

A substantial number of pharmacokinetic interaction studies did not report and analyze pharmacokinetic outcomes according to FDA guidance for bioequivalence studies.30 Future experiments of drug interactions must evaluate pharmacokinetic outcomes as geometric mean ratios with predefined margins of bioequivalence. Future studies of drug interactions must report pharmacokinetic outcomes as geometric mean ratios. This would allow statistically allow statistically significant as well as nonsignificant outcomes to be interpreted in terms of clinical significance, using predefined margins of bioequivalence.

Given the dearth of studies examining interactions between specific supplements and cardiovascular drugs, future clinical trials and observational studies that explore the effect of cardiovascular drugs should additionally assess the use of dietary supplements and include this in the reporting of results. One way to facilitate this would be to consider inclusion of inquiry about dietary supplement use and other CAM care in reporting guidelines such as CONSORT (CONsolidated Standards of Reporting Trials).

Phase I trials of cardiovascular drugs should include older populations and, if possible, a pharmacokinetic assessment that includes dietary supplement usage.

As subgroups were underrepresented in existing studies, future studies investigating supplement-drug interactions should examine vulnerable subgroups such as the elderly, those with compromised renal and liver functions, and patients with multiple comorbidities.

When possible, comparative effectiveness studies should include a statistical analysis for supplement–drug interactions, and the trials should be powered accordingly.

Until well-powered experimental studies are conducted to examine dietary supplement-drug coadministration, evidence from well-conducted prospective observational studies should be sought. Observational studies compliant with STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines should be powered appropriately to address predefined endpoints of both efficacy and safety in a naturalistic setting, where the population sampled is reflective of the population for which these data would be meaningful.106

Given the difficulty and resource-intensive nature of clinical trials, other sources of data should be considered to derive information regarding drug-dietary supplement interactions. Possibilities include synthesis of reports of adverse events made to both FDA and the Pharmacovigilance program at Health Canada. In addition, electronic health record linkages between databases of dietary supplement use and cardiovascular drug prescription may also add to the sparse evidence on supplement–cardiovascular drug interaction that currently exists.

Balluz LS, Kieszak SM, Philen RM, et al. Vitamin and mineral supplement use in the United States: results from the third National Health and Nutrition Examination Survey. Arch Fam Med. 2000;9(3):258-62.

National Institutes of Health. Exploring the Science of Complementary and Alternative Medicine. National Center for Complementary and Alternative Medicine. Third Strategic Plan 2011-2015. U.S. Department of Health and Human Services; 2011.